Waldenström's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (IgM MGUS) often precedes the development of WM. It is clinically difficult to distinguish WM from IgM MGUS, which may have a similar immunophenotype on examination of neoplastic cells but differs greatly in prevalence and prognosis. Thus, methods to better discriminate WM from IgM MGUS are needed to permit advances in diagnostic testing, and development of targeted therapies.